L-Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system which activates several subtypes of ionotropic and metabotropic receptors. The ionotropic receptors can be divided into three subtypes, NMDA, AMPA and kainate receptors, based on structural and pharmacological differences.
Impairment of glutamatergic neurotransmission has been implicated in the learning and memory loss observed in numerous neurological disorders such as e.g. Alzheimer's decease, senile dementia, stroke (McEntee and Crook, Psycopharmacology 111:391–401 (1993)). It is widely accepted that learning and memory is related to the induction of long-term potentiation (LTP) which is a stable increase in the synaptic strength following repetitive high frequency stimulations. Experimental studies have shown that increasing the synaptic response mediated by AMPA receptors enhances the induction of LTP (Arai and Lynch, Brain Research, 598:173–184 (1992)). For the reasons stated above, compounds that stimulates AMPA receptor response in the brain, may induce improvements in the intellectual behavior and performance.
Activation of AMPA receptors with L-glutamate or the selective agonist AMPA leads to a rapid receptor desensitization; i.e. the receptor channel fails to open despite the continued presence of agonist. It is therefore possible to obtain an increase of the synaptic strength by attenuating the AMPA receptor desensitization normally elicited by the endogenous neurotransmitter L-glutamate.
In 1990 Ito et al. reported (J. physiol., 424:533–543) that the nootropic drug aniracetam (N-anisoyl-2-pyrrolidinone) increased AMPA induced currents in oocytes injected with rat brain mRNA. In another study, it has been shown that 1-(1,3-benzodioxol-5-ylcarbonyl)-1,2,3,6-tetrahydropyridine, a compound that enhances synaptic transmission mediated by AMPA receptors, is effective at improving memory in experimental animals at a very high dose 120 mg/kg (Staubli et al., Proc. Natl. Acad. Sci. USA, 91:11158–11162 (1994)).
The benzothiadiazide cyclothiazide is a more potent and efficacious modulator of AMPA receptor current in-vitro than aniracetam (Johansen et al., Mol. Pharmacol. 48:946–955 (1995)). The effect of cyclothiazide on the kinetic properties of AMPA receptor currents appear to be by a different mechanism to that of aniracetam (Partin et al., J. Neuroscience 16:6634–6647 (1996)). However, cyclothiazide has no therapeutic potential for AMPA receptor modulation as it can not cross the blood-brain-barrier following peripheral administration. The low potency of know compounds also meets with higher demands for a high solubility due to the higher doses used for administration.